Studies on individuals and animals with severe genetic defects in serotonin function can shed light on the role of milder functional variants in serotonin genes in predisposing individuals to psychopathologies and to alcoholism. we have targeted patients with a positive family history or significant dysmorphology with severe mental retardation, pervasive developmental disorder, infantile autism, obsessive compulsive disorder, disruptive behavioral disorder or other disrupted behaviors which are presumptively under serotonergic influence. We are identifying probands for family studies by measuring the serotonin metabolite 5HIAA in cerebrospinal fluid. Probands and family members receive a detailed neurologic and psychiatric assessment and familial transmission and comorbidity is concurrently assessed. Subjects with aberrant serotonin function and their families will be the focus for genetic linkage analysis using dispersed probes and direct studies (for example sequencing) of candidate genes such as tryptophan hydroxylase (TPH). We are also studying animal behavioral genetic models in which serotonin function may be perturbed. A TPH polymorphism was found to be associated with low CSF 5HIAAA and suicidality in impulsive alcoholic Finns. In the mouse, TPH was identified as a quantitative trait locus (QTL) for sleep time following ethanol injection.